Introduction
Brain metastases are one of the most common intracranial
malignancies that remain a substantial source of
morbidity and mortality in cancer patients.[] The incidence
of brain metastases has been increasing over
the last few years.[,]
The recent novel advances in the management of
carcinomas have increased the demand for a safe and
effective control of cerebral metastases.[] Whole Brain Radiotherapy (WBRT) has remained one of the most
widely used treatment option in patients with non-solitary
brain metastases, although recent clinical experiences
permitted local control of non-solitary brain metastases
using Stereotactic Radio Surgery (SRS).[] As
a focal, highly precise treatment option, SRS provides
many benefits, including a short treatment timeline, a
low probability of normal tissue complication, and a
high probability of treated lesion control.[] The use of
SRS and imaging accessibility has led to a dramatic reduction in mortality related to intracranial tumor progression.[,] Recent studies have indicated GKRS as
an effective treatment modality for non-solitary brain
metastases with good local control and lesser neurological
and neuropsychological side-effects.[,]
However, the current literature is relatively devoid of
information concerning extensive metastatic disease, it
is necessary to determine the effectiveness of SRS treatment
for patients with non-solitary brain metastases.
In this regard, few studies have evaluated the effectiveness
of GKRS in the management of non-solitary brain
metastases in Indian setting.[-]
The management of choice of single metastasis is still
surgical, with or without adjuvant WBRT/SRS. Hence,
the prognosis and overall survival defers significantly
when compared to two or more metastatic lesions.[]
For the patients with two or more metastatic lesions the
overall survival did not show any significant difference
concerning the number of lesions in the brain. The
management of these patients is usually non-surgical
with WBRT/WBRT+GKRS/GKRS alone.[]
Recently, Yamamoto reported a prospective,
non-randomised multicenter study of 1194 patients
with tumor number up to 10 and treated with GKRS
alone. Only 17 percent patients had more than four
lesions in the brain. The median overall survival after
GKRS was significantly longer in patients with single
tumor than those with two or more tumors. Further,
the median overall survival for the two groups of patients
with more than one tumor (2-4 tumors vs. 5-10
tumors) was the same.[]
Based upon this study, which suggested a significant
management change between patients with single
lesion and those with two or more lesions, it was decided
to analyze the chances of overall median survival
in patients with two or more lesions. This kind of study
has not been reported in the literature. Therefore, the
present study aimed to assess the effectiveness of GKRS
in patients with non-solitary brain metastases.
Methods
Study Design
A retrospective study was conducted to review case
records of the patients diagnosed with non-solitary
brain metastases. The data of the patients who were
treated with GKRS in Gamma Knife centre, All India
Institute of Medical Sciences, New Delhi, India, were
included in this study. Seventy nine patients received
GKRS for brain metastasis from the period of 2002 to
2013.
Inclusion criteria were as follows:
1. Two or more metastatic lesions detected by MRI
and confirmed by neuro oncologist
2. Age >18 years
3. Known histological proven primary cancer
Exclusion criteria were:
1. Unfeasible GKS treatment or an overriding indication
for surgery because of high ICP or the need to
obtain a histological diagnosis;
2. Prior treatment of brain metastases with GKRS
3. Previous treatment for single brain metastatic lesion
4. Contradicted MRI findings
Study Procedure
The demographic and clinical information was extracted
from the clinical records, which included gender,
age, location of lesions, tumor histology, number of
metastases, Kanofsky Performance Status (KPS) score,
information regarding previous WBRT, status of the
primary tumor, status of extra-cranial metastasis, peripheral
dose, tumor volume, Recursive Partition Analysis
(RPA). The RPA helps to guide clinical decision
making for brain metastases. It divides patients with
brain metastases into three broad categories based on
patient age, KPS, presence of extracranial metastases,
and the status of the primary tumor control.[] RPA
was used because it has been shown to be of prognostic
value in patients with brain metastases, and has been
invariably used in various studies that have evaluated
the effectiveness of GKRS.[]
GKRS was performed using Leksell B and Leksell
Perfexion model. Treatment was planned by using
Electa's Gamma Plan Software. In this regard, RTOG
95-08 [] guidelines, as well as parameters, such as
total number of metastases, tumor volume, and prior
WBRT were considered for the dose selection.
Overall Survival was defined as the time duration
between GKRS treatment and death. The survival time
data were obtained by asking the caregivers using telephonic
or postal communication.
Statistical Analysis
The Kaplan-Meier analysis was performed to estimate
the overall survival time and the survival duration for
the patients" subgroups. All statistical analyses were
performed using SPSS for Windows, Version 19 (SPSS
Inc., Chicago, IL, USA).
Results
Seventy nine patients received GKRS for brain metastasis
between 2002 and September 2013. Thirty two
patients (40.5%) had single metastatic lesion, and 47
patients (59.4%) had non-solitary lesions (range: 2 to
13). Of the 47 patients, only 40 patients whose date of
death or clinical status could be established by postal
or telephonic communication were included in the
study.
The clinical and demographical details of patients
are presented in Table 1. The median age of patients at
the date of GKRS was 54 years (range 35 to 76 years). In
this analysis, 131 lesions were treated in 40 patients. Fifty
eight lesions (44.28%) were present in the frontal lobes.
Table 1. Clinical and demographic characteristics of the
patients (N=40)
In majority of the patients, metastasis initiated from
breast carcinoma (42.5%). At the time of GKRS, 11 patients
(27.5%) had KPS less than 70, while eight patients
(20%) had KPS score of 90 or more. Extracranial tumor
was present in eight cases. Of the 40 cases, eight patients
had received prior WBRT while the remaining 32 had
not received any treatment before GKRS. In 22 cases
(55%), the primary tumor was controlled (Table 1).
Table 2 reveals the radiological parameters of the
present study. Most of the patients had two or three
lesions (82.5%), while only three patients (7.5%) had
more than five lesions. The planned tumor volume
(PTV) ranged between 0.018 cm3 and 39.1 cm3. The
median dose prescribed was 20 Gy (range; 8?25 Gy).
Table 2. Radiosurgical parameters
The distribution of the RPA score for patients is also
shown in Figure 1. There were 15 patients (37.5%) in
RPA Class I, 14 patients (35%) in RPA Class II and 11
patients (27.5%) in RPA Class III (Fig. 1).
Fig. 1. Number of the patients in different categories of
RPA.
The results obtained from survival analysis indicated
that the median survival time for different RPA
scores was significantly different. The median survival
was three months in class III and four months in classes
II and I (Table 3).
Table 3. RPA classification of the patients and median
survival
The median overall survival was four months (range
1 to 12 months). The overall survival curve is shown
in Figure 2. Twenty two patients (55%) succumbed to
their extracranial disease, 17 patients (42.5%) died because
of progressive intracranial disease and one patient (2.5%) survived till twelve months. The survival
curves are shown in Figure 3.
Fig. 2. Kaplan-Meier curve showing the overall survival
rate.
Fig. 3. Kaplan-Meier curve showing cumulative survival
rate stratified by RPA class.
Discussion
Non-solitary brain metastases (BMs) have a poor prognosis.
Hence, estimation of overall survival is significant
when deciding on treatment protocol.[] Therefore,
this study aimed to evaluate the effectiveness of Gamma Knife Radio Surgery (GKRS) in patients with
non-solitary brain metastases and role of RPA classification
in overall survival in these patients.
The descriptive findings of present study showed
that breast cancer was most likely to present with nonsolitary
brain metastases, followed by lung cancer.
Most of the previous evidences show that most of brain
metastases initiate from lung cancer.[,] One explanation
for such observation may be due to that there
were fewer men than women in the present study.[]
In addition, there is evidence that the cases with breast
cancer with distant involvement is increasing.[,]
In the present study, the most common location of lesion
was found to be in the frontal lobe which is also in
line with previous studies.[]
The present study showed an increased overall
survival in patients with brain metastases after GKRS
which is in line with findings of previous study.[-]
In a retrospective analysis of 5216 case records, Azimi
et al.[] have reported that GKRS helped in adequately
controlling brain metastasis and thus prolonging overall
survival. Other studies have also documented an
excellent effectiveness of GKRS in treatment of nonsolitary
brain metastases.[-]
The median overall survival of the patients was four
months. Higuchi et al.[] and Hasegwa et al.[] have
reported seven to eight months of survival in patients
after GKRS treatment of brain metastases. Yamamoto
et al.[] in two patients with two tumors has reported
survival of 3.5 and 5.3 months. It should be noted that
most of the patients who were treated in this centre were referred case. Hence, the late presentation for the
treatment may be a parsimonious reason for low survival
rate in patients in present study.
Concerning RPA classification and patients" survival,
this study also correlates with the earlier findings
which suggested a significant difference in the overall
survival among patients who differed in RPA classification.
Salvetti et al. analyzed 96 patients with five or
more metastatic lesions and showed a significant association
between RPA class and overall survival.[]
Grandhi et al.[] and Sanghavi et al.[] have found
significant difference in survival of different RPA category
patients. The RPA classification is based on patient
age, KPS, presence of extracranial metastases, and
the status of primary tumor control.[] These factors
are critical in predicting overall survival in patients
with non-solitary brain metastases. Therefore, RPA has
been shown to be of prognostic value in patients with
brain metastases.[]
In our study also, only seven patients (17 %) had
more than four lesions. On statistical analysis, it was
further confirmed that the number of lesions did not
alter the median survival significantly, which could
be attributed to the progression of the primary carcinoma.
Whole brain radiotherapy (WBRT) has a long list of
toxic effects which include scalp erythema, reversible
hair loss, fatigue, hyper pigmentation, irritable behavior
and anorexia. These may develop over a period of 5
to 10 weeks after WBRT.[] Long duration side effects
of WBRT are usually not seen in the patients of Brain
metastasis due to their short overall survival. However,
DeAngelis et al. reported 12 patients who developed
dementia, urinary incontinence and ataxia within five
months to 36 months of treatment with WBRT.[,]
On the other hand, GKRS uses collimated high energy
Gamma rays directed to the area of interest with
minimal exposure of the normal brain and is usually
administered as a single dose. As such, the chances of
complications are minimal with GKRS and acute side
effects are negligible if any.
Delayed toxicity in the form of neurocognitive decline,
seizures, sensory-motor deficits, dysarthria, cerebellar
ataxia and others were studied prospectively and
reported by Yamamoto et al. but were not found to be
significant in patients with multiple metastases.[] In
the present study, the clinical records of the patients
have been evaluated retrospectively and almost all the
patients died at the time of this study. None of the patients
visited the hospital in the follow up period. This
behavior could be ascribed to the detailed pre-GKRS counseling about the prognosis and natural course of
the disease. Hence, no toxicity data could be collected
from the records. These patients had a very short overall
survival and neurotoxin features are a late development
in the clinical course of patients receiving GKRS.
Therefore, it was not possible to evaluate these delayed
changes in this study.
It is clear from the literature that deferring WBRT
and using SRS as a frontline treatment for patients with
non-solitary brain metastases has gained widespread
popularity. GKRS is better than conventional radiotherapy
owing its efficacy concerning improved cognitive
functioning [,] non-invasive nature, faster
recovery, shorter hospital stay and cost-effectiveness.
[] In the Indian context, the major discordance exists
between practice patterns and the lack of facilities of
SRS in Indian medical hospitals.[]
Limitations
In this study, GKRS was found to be a safe and effective
upfront and salvage treatment for patients with ≥2 brain
metastases; however, there were principle weaknesses
in this study. The first weakness is its retrospective nature
and the inherent limitations of this methodology.
Second, the sample size is small and a larger study is
suggested for more authoritative recommendations.
Conclusion
Our series shows that GKRS is a valuable, effective,
and well-tolerated treatment modality for patients with
non-solitary intracranial metastases. The findings also
showed that a high proportion of patients succumbed
to death with other regions rather than the metastases.
Thus, the implementation of an effective plan of GKRS
can help in improving the overall survival of the patients
with brain metastases.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: Approved by All India Institute
of Medical Sciences Ethics committee.
Financial Support: No financial support was sought.
Authorship contributions: Concept - N.P.; Design - N.P.,
M.S., S.S.K.; Supervision - M.S.; Funding - None; Materials
- N.P., M.S., S.S.K.; Data collection and/or processing - N.P.;
Data analysis and/or interpretation - N.P., M.S., S.S.K.; Literature
search - N.P., M.S.; Writing - N.P.; Critical review
- M.S., S.S.K., N.P.
References
Hardesty DA, Nakaji P. The Current and Future Treatment
of Brain Metastases. Front Surg 2016;3:30.
Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases.
Curr Oncol Rep 2012;14(1):48-54.
Fox BD, Cheung VJ, Patel AJ, Suki D, Rao G. Epidemiology
of metastatic brain tumors. Neurosurg Clin N
Am 2011;22(1):1-6, v.
Kraft J, Zindler J, Minniti G, Guckenberger M, Andratschke
N. Stereotactic Radiosurgery for Multiple
Brain Metastases. Curr Treat Options Neurol
2019;21(2):6.
Nieder C, Grosu AL, Gaspar LE. Stereotactic radiosurgery
(SRS) for brain metastases: a systematic review.
Radiat Oncol 2014;9:155.
Badiyan SN, Regine WF, Mehta M. Stereotactic Radiosurgery
for Treatment of Brain Metastases. J Oncol
Pract 2016;12(8):703-12.
Chao ST, De Salles A, Hayashi M, Levivier M, Ma L,
Martinez R, et al. Stereotactic Radiosurgery in the
Management of Limited (1-4) Brain Metasteses: Systematic
Review and International Stereotactic Radiosurgery
Society Practice Guideline. Neurosurgery
2018;83(3):345-53.
Halasz LM, Rockhill JK. Stereotactic radiosurgery and
stereotactic radiotherapy for brain metastases. Surg
Neurol Int 2013;4(Suppl 4):S185-91.
Bir SC, Ambekar S, Nanda A. Long term outcome of
Gamma Knife radiosurgery for metastatic brain tumors.
J Clin Neurosci 2014;21(12):2122-8.
Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S,
Tago M, et al. Phase 3 trials of stereotactic radiosurgery
with or without whole-brain radiation therapy for 1 to 4
brain metastases: individual patient data meta-analysis.
Int J Radiat Oncol Biol Phys. 2015;91(4):710-7.
Deora H, Tripathi M, Tewari MK, Ahuja CK, Kumar
N, Kaur A, et al. Role of gamma knife radiosurgery in
the management of intracranial gliomas. Neurol India
2020;68(2):290-8.
Rathod S, Munshi A, Agarwal JP. Practice of stereotactic
body radiotherapy in a developing country: Perception,
aspiration, and limitation - A survey. Indian J
Cancer 2016;53(1):135-7.
Bhatnagar AK, Flickinger JC, Kondziolka D, Lunsford
LD. Stereotactic radiosurgery for four or more intracranial
metastases. Int J Radiat Oncol Biol Phys
2006;64(3):898-903.
Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ,
Maruyama Y, Kryscio RJ, et al. A randomized trial of
surgery in the treatment of single metastases to the
brain. N Engl J Med 1990;322(8):494-500.
Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi
Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901):
a multi-institutional prospective observational study.
Lancet Oncol 2014;15(4):387-95.
Gaspar L, Scott C, Rotman M, Asbell S, Phillips T,
Wasserman T, et al. Recursive partitioning analysis
(RPA) of prognostic factors in three Radiation Therapy
Oncology Group (RTOG) brain metastases trials.
Int J Radiat Oncol Biol Phys 1997;37(4):745-51.
Gaspar LE, Scott C, Murray K, Curran W. Validation
of the RTOG recursive partitioning analysis (RPA)
classification for brain metastases. Int J Radiat Oncol
Biol Phys 2000;47(4):1001-6.
Andrews DW, Scott CB, Sperduto PW, Flanders AE,
Gaspar LE, Schell MC, et al. Whole brain radiation
therapy with or without stereotactic radiosurgery
boost for patients with one to three brain metastases:
phase III results of the RTOG 9508 randomised trial.
Lancet 2004;363(9422):1665-72.
Liu Q, Tong X, Wang J. Management of brain metastases:
history and the present. Chin Neurosurg J 2019;
5(1):1.
National Cancer Institute. Available at: http://www.
cancer.gov/. Accessed Feb 08, 2020.
Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence
of brain metastases in a cohort of patients with
carcinoma of the breast, colon, kidney, and lung and
melanoma. Cancer 2002;94(10):2698-705.
Azimi P, Shahzadi S, Bitaraf MA, Azar M, Alikhani M,
Zali A, et al. Brain metastases in cancer patients attending
a Gamma Knife Center: A study from a single
institute in Iran. Asian J Neurosurg 2017;12(3):529-33.
Johnson RH, Chien FL, Bleyer A. Incidence of breast
cancer with distant involvement among women in the
United States, 1976 to 2009. JAMA 2013;309(8):800-5.
Frisk G, Svensson T, Bäcklund LM, Lidbrink E,
Blomqvist P, Smedby KE. Incidence and time trends
of brain metastases admissions among breast cancer
patients in Sweden. Br J Cancer 2012;106(11):1850-3.
Wang G, Xu J, Qi Y, Xiu J, Li R, Han M. Distribution
Of Brain Metastasis From Lung Cancer. Cancer
Manag Res 2019;11:9331-8.
Salvetti DJ, Nagaraja TG, McNeill IT, Xu Z, Sheehan
J. Gamma Knife surgery for the treatment of 5 to 15
metastases to the brain: clinical article. J Neurosurg
2013;118(6):1250-7.
Grandhi R, Kondziolka D, Panczykowski D, Monaco
EA 3rd, Kano H, Niranjan A, et al. Stereotactic radiosurgery
using the Leksell Gamma Knife Perfexion unit
in the management of patients with 10 or more brain
metastases. J Neurosurg 2012;117(2):237?45.
Sanghavi SN, Miranpuri SS, Chappell R, Buatti JM,
Sneed PK, Suh JH, et al. Radiosurgery for patients with
brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method.
Int J Radiat Oncol Biol Phys 2001;51(2):426-34.
Singh S, Sarin A, Semwal M, Bhatnagar S, Gill M,
Sharma S. Gamma knife-based stereotactic radiosurgery
boost after whole-brain radiotherapy in patients
with up to three brain metastases: Effects on
survival, functional independence, and neurocognitive
function. Int J Neurooncol 2019;2(2):101.
Yomo S, Hayashi M. A minimally invasive treatment
option for large metastatic brain tumors: long-term results
of two-session Gamma Knife stereotactic radiosurgery.
Radiat Oncol 2014;9:132.
Yamamoto M, Ide M, Jimbo M, Aiba M, Ito M, Hirati
T, et al. Gamma Knife Radiosurgery with Numerous
Target Points for Intracranially Disseminated Metastases.
In: Kondziolka D, editor. Radiosurgery 1997.
Basel: Karger; 1998. p. 94-109.
Aoyama H, Tago M, Shirato H; Japanese Radiation
Oncology Study Group 99-1 (JROSG 99-1) Investigators.
Stereotactic Radiosurgery With or Without
Whole-Brain Radiotherapy for Brain Metastases: Secondary
Analysis of the JROSG 99-1 Randomized
Clinical Trial. JAMA Oncol 2015;1(4):457-64.
Sharma B S, Borkar S A. Current and future management
of brain metastasis (Progress in Neurological
Surgery). Indian J Med Res 2013;137(2):399-400.
Higuchi Y, Yamamoto M, Serizawa T, Aiyama H, Sato
Y, Barfod BE. Modern management for brain metastasis
patients using stereotactic radiosurgery: literature
review and the authors" gamma knife treatment experiences.
Cancer Manag Res 2018;10:1889-99.
Hasegawa T, Kato T, Yamamoto T, Iizuka H, Nishikawa
T, Ito H, et al. Multisession gamma knife surgery for large
brain metastases. J Neurooncol 2017;131(3):517-24.
Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T,
Barfod BE, et al. A case-matched study of stereotactic
radiosurgery for patients with multiple brain metastases:
comparing treatment results for 1-4 vs ? 5 tumors: clinical article. J Neurosurg 2013;118(6):1258-68.
Boldrey E, Sheline G. Delayed transitory clinical manifestations
after radiation treatment of intracranial tumors.
Acta Radiol Ther Phys Biol 1966;5:5-10.
DeAngelis LM, Delattre JY, Posner JB. Radiation-induced
dementia in patients cured of brain metastases.
Neurology 1989;39(6):789-96.
Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF,
Kornguth DG, et al. Neurocognition in patients with
brain metastases treated with radiosurgery or radiosurgery
plus whole-brain irradiation: a randomised
controlled trial. Lancet Oncol 2009;10(11):1037-44.
Yamamoto M, Serizawa T, Higuchi Y, Sato Y, Kawagishi
J, Yamanaka K, et al. A Multi-institutional Prospective
Observational Study of Stereotactic Radiosurgery for
Patients With Multiple Brain Metastases (JLGK0901
Study Update): Irradiation-related Complications
and Long-term Maintenance of Mini-Mental State
Examination Scores. Int J Radiat Oncol Biol Phys
2017;99(1):31-40.
Linskey ME, Andrews DW, Asher AL, Burri SH,
Kondziolka D, Robinson PD, et al. The role of stereotactic
radiosurgery in the management of patients
with newly diagnosed brain metastases: a systematic
review and evidence-based clinical practice guideline.
J Neurooncol 2010;96(1):45-68.
Habets EJ, Dirven L, Wiggenraad RG, Verbeek-de
Kanter A, Lycklama À Nijeholt GJ, et al. Neurocognitive
functioning and health-related quality of life
in patients treated with stereotactic radiotherapy for
brain metastases: a prospective study. Neuro Oncol
2016;18(3):435-44.
Manir KS, Mukherjee A, Banerjee D, Basu A, Basu S,
Guha S. Clinicians view and practice pattern on the
use of stereotactic radiosurgery in brain metastases:
A survey among Indian radiation oncologists. Int J
Neuro Oncol 2018;1(1):40-5
